JP7055840B2 - Composition - Google Patents

Description

The present invention relates to improved omega-3 fatty acid formulations. More specifically, the invention relates to an improved emulsion of ω-3 fatty acids or pre-emulsion concentrate formulations.

Various ω-3 fatty acids and their uses, including pharmaceutical products, nutritional products or dietary supplement products, are known in the art. See, for example, US Pat. No. 5,502,077, US Pat. No. 5,656,667 and US Pat. No. 5,698,594.

One pharmaceutical product is known as LOVAZA® (activity name "ω-3-acid ethyl ester") and trigluceri in very high (> 500 mg / dL) trigluceride levels in adult patients. For dietary doses of 4 g per day (either as a single 4 g dose (4 capsules) or as 2 g of 2 doses (2 capsules given twice daily)) to reduce dosage levels. It is a lipid regulator approved by the US Food and Drug Administration as an adjunct.

LOVAZA® is commercially available as a liquid-filled gel capsule for oral administration. Each 1 gram capsule of LOVAZA® contains at least 900 mg of ethyl ester of ω-3 fatty acid. These are primarily combinations of ethyl esters of EPA (about 465 mg) and DHA (about 375 mg). LOVAZA® capsules also contain the following inactive ingredients: 4 mg α-tocopherol (in a carrier of vegetable oil containing soybean oil), and gelatin, glycerol and purified water (components of the capsule shell).

Expert Panel on Detection, Assessment, and Treatment of High Blood Cholesterol, 3rd Report, Expert Committee on the Detection, Evaluation and Treatment of Adult Hypercholesterolemia in the National Cholesterol Education Program. , NIH Publishing No. 02-5215 (September 2002) (also known as "NCEP ATP III"), triglycerides are normal (<150 mg / dL), high but borderline (150-199 mg /). It is classified as dL), high (200-499 mg / dL), and very high (≧ 500 mg / dL). LOVAZA® has been demonstrated to be effective in reducing triglycerides in very high triglyceride populations, but triglycerides in many patients are still above normal levels.

It would be advantageous to increase the therapeutic effect of an omega-3 fatty acid composition such as LOVAZA®, for example to provide an improvement in therapies such as a decrease in elevated triglycerides. One approach to increasing the therapeutic effect of orally administered drugs is to increase the exposure or absorption of the drug after oral administration. Therefore, it may be advantageous to increase the exposure of ω-3 fatty acids after oral administration. Provides increased therapeutic efficacy, eg, maintaining or possibly reducing dosage and / or frequency (eg, number and / or size of capsules) without increasing dose loading, such as pill or capsule loading. It would be especially advantageous if it could be done. Reducing the dosing load allows, for example, easier dosing, improved patient compliance, reduced side effects such as ambiguity, reduced caloric intake, and among some ω-3 products. Exposure to any undesired component that may be present is reduced, and / or the cost of therapy is reduced.

The literature includes various references that disclose studies involving fish oil and / or omega-3 fatty acid compositions (compositions that can or can be emulsified in some embodiments). For example, Gariaova et al. Nutrition Journal 2007, 6: 4 (http://www.nutritionj.com/contents/6/1/4); Raatz et al. Jnl of the American Dietetic Association June 2009 Vol 109 No. 6 1076-1081; Mishra et al., Issued September 4, 2001. US Pat. No. 6,284,268; International Publication No. 2008/101344; and Bryhn, M. et al. et al. , Prostaglandins, Leukotrienes and Essential Fatty Acids 75: 19-24 2006.

The present invention relates to novel emulsion compositions and pre-emulsion concentrate compositions.

In one embodiment, the present invention comprises an aqueous phase comprising an aqueous liquid, an oil phase comprising an ω-3 fatty acid oil, and a surfactant, the emulsion having a central particle size of from about 100 nm to about 3 μm. The present invention relates to an emulsion composition having a median partial size).

In another embodiment, the invention comprises an aqueous liquid that supplies from about 65 to about 80% by weight water and from about 15 to about 30% by weight ω-3 fatty acid oil, based on the total weight of the emulsion composition. The present invention relates to an emulsion composition comprising from about 5 to about 10% by weight of a surfactant.

In another embodiment, the invention comprises an omega-3 fatty acid oil and a surfactant, wherein the preconcentrate can be contacted with an aqueous liquid to form an emulsion having a central particle size of about 100 nm to about 3 μm. Concerning pre-concentrate composition.

Another aspect of the invention is about 60-about 85% by weight of the omega-3 fatty acid oil and about 15-about 40% by weight, based on the total weight of the ω-3 fatty acid oil and the surfactant in the composition. The present invention relates to a pre-emulsion concentrate composition comprising the above-mentioned surfactant.

In another aspect, the invention relates to an emulsion formed by contacting an aqueous liquid with the pre-emulsion concentrate composition of the invention.

In another aspect, the invention relates to an oral dosage form, such as a pharmaceutical product, a nutritional product or a dietary supplement, comprising the emulsion or pre-emulsion concentrate composition of the present invention.

The present invention is an emulsion or emulsion of the present invention for the production of pharmaceutical products, nutritional products or dietary supplements suitable for the treatment of any disease, condition or the same type that can use an omega-3 fatty acid oil. Also related to the use of pre-concentrate compositions.

The present invention administers the emulsion or pre-emulsion concentrate composition of the present invention to a subject in need thereof for the treatment of any disease, condition or the like in which an omega-3 fatty acid oil can be used. It also relates to treatment methods that include doing.

In another aspect, the invention comprises oral administration of the emulsion or pre-emulsion concentrate composition of the invention to a subject, the oral absorption of which is compared to the oral absorption of the omega-3 fatty acid oil after oral administration. It relates to a method of increasing oral absorption of omega-3 fatty acids in a subject in need of increased treatment with omega-3 fatty acids.

Other aspects of the invention will be understood in light of the present disclosure.

Emulsion and pre-emulsion concentrate compositions of the invention comprising LOVAZA® ω-3 acid ethyl ester (particularly those having or supplying an emulsion center particle size of about 100 nm to about 3 μm in preclinical studies. ) Have been found to improve exposure or absorption of the major composition of ω-3 fatty acids after oral administration.

The emulsion and / or pre-emulsion concentrate composition of the present invention is
Increasing oral absorption (exposure), oral bioavailability, and / or oral efficacy of one or more components of omega-3 fatty acids as compared to ω-3 fatty acid oils.
Providing an improved treatment method, eg, providing treatment for elevated triglycerides, such as a decrease in elevated triglycerides (eg,> 500 mg / dL, or ≧ 200 mg / dL, or ≧ 150 mg / dL triglyceride levels), and. / Or can allow a reduction in the dosing level and / or frequency of the omega-3 fatty acid oil required to achieve effective therapy (eg, reduction in the number and / or size of capsules).

Specific description of the invention

Unless otherwise stated or required in context, it is defined as follows:

As used herein with reference to the components of a composition, "one (a)", "one (an)" and "the" include one or more components (the). For example, "surfactant" includes one or more surfactants and the like).

When used herein as a reference to a value or range of values, "about" includes the values explicitly stated (eg, "about 100 nm to about 3 μm" specifically includes the range 100 to 3 μm, etc.).

An embodiment comprising the described features will be, or will be, essentially also from those features (eg, a composition comprising the described components will also be essentially from those components. Will be, or will be composed of them).

Variations such as the words "comprise" and "comprises" and "comprising" suggest inclusion of the stated integer values or steps or groups of integer values, but other It will be understood that it does not exclude an integer value or process or a group of integer values or processes.

The present invention includes all combinations of specific groups and preferred groups described herein, eg, a "mixture" of the described components is between and / or specific components. It comprises a mixture in the group (eg, a mixture of acids, glycerides, and alcohol esters includes 1) a mixture of acids, 2) a mixture of acids, glycerides, and alcohol esters; etc.).

The emulsion of the present invention refers to the conventional meaning for dispersion including an aqueous phase and an oil phase. The aqueous phase includes a water-containing medium (preferably a liquid medium), including, for example, water itself or other aqueous liquids. The oil phase contains at least one hydrophobic (lipophilic) organic component (eg, ω-3 fatty acid oil).

The emulsion of the present invention is an oil-in-water (o / w) emulsion, the oil phase contains ω-3 fatty acid oil and is dispersed in the aqueous phase, and the oil phase has the conventional meaning of "fine particles" or "droplets". Can be described in. However, emulsions can, to a lesser extent, exhibit the characteristics of water-in-oil (w / o) emulsions or other dispersions. Therefore, the emulsion of the present invention can be substantially described as an oil-in-water emulsion.

In a preferred embodiment, the dispersed phase has a central particle size in the range of about 100 nm to about 3 μm (including, for example, about 100 nm to about 1 μm, such as about 100 nm to about 300 nm). As used herein, "central particle size" refers to the 50th percentile value of the cumulative size distribution. In some embodiments, the emulsion has a x90 particle size of about 5 μm or less (eg, about 1.5 μm or less) (ie, the 90th percentile value of the cumulative size distribution). In some embodiments, the dispersed phase has both the aforementioned central particle size and x90 particle size. Particle size is determined as described below in the experimental section.

In some embodiments, the emulsions of the invention exhibit one or more of the following properties:
a) Thermodynamically stable, i.e., at room temperature (20-30 ° C, especially 25 ° C), for example over a long period of time, without optically observable separation or substantial formation of larger particle sizes or precipitates. It remains stable. The preferred emulsion remains stable at ambient temperature for a period of at least 3 hours, more preferably at least 6 hours, most preferably at least 24 hours. And / or b) Formed easily or spontaneously with minimal agitation and mixing.

As used herein, an "emulsion pre-concentrate" can form an emulsion upon contact with water (eg, addition to or mixing with water or an aqueous liquid). It is a system that can be done. When the pre-emulsion concentrate is contacted with water, the emulsion preferably formed from the pre-emulsion of the present invention is spontaneously or substantially spontaneously formed. That is, the emulsion is formed without the need for substantial energy such as heating or the use of high shear or other substantial agitation. For example, the emulsion can be formed after oral administration of the preconcentrate under existing conditions in the stomach. The resulting emulsion can be generally as defined herein, or as defined by any particular embodiment. For example, in some embodiments, the resulting emulsion has a central particle size of about 100 nm to about 3 μm (including, for example, about 100 nm to about 1 μm, including about 100 nm to about 300 nm). The resulting emulsion can further have a x90 particle size of about 5 μm or less (eg, about 1.5 μm or less).

ω-3 Fatty Acid Oil The emulsion and pre-emulsion concentrate composition of the present invention comprises an ω-3 fatty acid oil containing one or more ω-3 fatty acids.

As used herein, "ω-3 fatty acid" includes natural or synthetic free ω-3 fatty acids and their derivatives, unless expressly excluded. Similarly, references to a particular omega-3 fatty acid include its derivatives, unless explicitly excluded.

Suitable ω-3 fatty acid derivatives include pharmaceutically acceptable esters of ω-3 fatty acids, conjugates (eg, Zaloga et al., US Patent Application No. 2004/0254357, Horrobin et al., US Pat. No. 6,245,811). See), precursors, salts or other derivatives.

Specific examples of ω-3 fatty acids include
a) ω-3 polyunsaturated long-chain free fatty acids (eg, eicosapentaenoic acid C20: 5 (“EPA”), docosahexaenoic acid C22: 6 (“DHA”), α-linolenic acid), ω-3 poly. Polyunsaturated free fatty acids (eg, having an aliphatic end of 12-22 carbons, especially 18-22 carbons), and
b) Esters of ω-3 fatty acids (eg, ω-3 polyunsaturated free fatty acids, eg long chains) with glycerol, such as monoglycerides, diglycerides and triglycerides.
c) With ω-3 fatty acids (eg ω-3 polyunsaturated free fatty acids, eg long chains) and esters of primary alcohols, secondary alcohols or tertiary alcohols, such as methyl and ethyl esters of fatty acids. including. The omega-3 fatty acid oil can contain a mixture of any of the above.

Preferred ω-3 fatty acids are polyvalent unsaturated long chain free fatty acids, the triglycerides thereof, which include, for example, EPA, DHA, triglycerides of EPA, triglycerides of DHA, ethyl esters of EPA, ethyl esters of DHA, and mixtures thereof. Ethyl ester, and a mixture thereof.

The ω-3 fatty acid oil may be in pure form or, for example, fish oil (also known as marine oil), preferably refined fish oil concentrate, egoma oil, marine microalga oil, or flax (flaxseed), chia, kiwi. Ω-3 fatty acids can be included as constituents of oils such as marine or vegetable oils (including their concentrates) such as oils from fruit, kokemomo, camelina, sliphiyu or black strawberry seeds. Oils containing high concentrations of ω-3 fatty acids, such as fish oil or mixtures thereof, are particularly useful. The term "ω-3 fatty acid oil" includes these forms.

Commercial examples of ω-3 fatty acid oils suitable for use in the present invention are Incromega F2250, F2628, E2251, F2573, TG2162, TG2779, TG2928, TG3525 and E5015 (Croda International, Yorkshire, England), and EAX6000. Includes EPAX4510TG, EPAX2050TG, K85TG, K85EE, K80EE and EPAX7010EE) (Pronova Biocare, 1327 Lysaker, Norway).

In some embodiments, the omega-3 fatty acid oil comprises a mixture of fatty acids. In various embodiments, the fatty acid can be only the ω-3 fatty acid, or one or more in combination with one or more non-ω-3 fatty acids (eg, ω-6 fatty acids, ω-9 fatty acids, etc.). Can contain ω-3 fatty acids. In some embodiments, the mixed fatty acid composition is at least 25% by weight, preferably at least 40% by weight, more preferably at least 50% by weight, even more preferably at least 60% by weight, with respect to the weight of the composition. , More preferably at least 70% by weight, most preferably at least 80% by weight, or even more preferably at least 90% by weight.

In some embodiments, the ω-3 fatty acid oil is at least 25% by weight, preferably at least 40% by weight, more preferably at least 50% by weight, even more preferably, with respect to the weight of the total fatty acids in the oil. One at a total concentration of at least 60% by weight, even more preferably at least 70% by weight, most preferably at least 80% by weight, or even more preferably at least 90% by weight (eg, at least 95% to 100% by weight). Or it contains multiple ω-3 fatty acids. The composition can include pure omega-3 fatty acids (s).

Preferably, the omega-3 fatty acid oil is at least 50% by weight, more preferably at least 60% by weight, even more preferably at least 70% by weight, most preferably about by weight, with respect to the weight of the total fatty acids in the oil. It contains at least 80% EPA and DHA, such as 84%.

The ω-3 fatty acid oil is about 5 to about 100% by weight, more preferably about 25 to about 75% by weight, even more preferably about 40 to about 55% by weight, with respect to the weight of the total fatty acids in the oil. And most preferably can contain about 46% EPA by weight.

The omega-3 fatty acid oil is about 5 to about 100% by weight, more preferably about 25 to about 75% by weight, even more preferably about 30 to about 60% by weight, with respect to the weight of the total fatty acids in the oil. And most preferably by weight can consist of about 38% DHA.

In other embodiments, the percentages above are due to the weight of the omega-3 fatty acid oil.

The weight percent is preferably based on the ethyl ester form of the ω-3 fatty acid (and other fatty acids, if any), but other forms may be based on the free acid or ester form as utilized in accordance with the present invention. .. As used herein, references to "EPA" and "DHA" include free acid forms and ester forms (eg, including ethyl ester forms in particular), unless otherwise stated.

In some embodiments, the EPA and DHA are 99: 1 to 1:99, such as 1: 4 to 4: 1, such as 1: 3 to 3: 1, or, for example, 1: 2 to 2: 1. It is a weight ratio of DHA. The omega-3 fatty acid oil can also contain pure EPA or pure DHA.

In some embodiments, the omega-3 fatty acid oil is the composition listed in US Pat. No. 5,502,077, US Pat. No. 5,656,667 or US Pat. No. 5,698,594. be.

If the oil is dispersible and emulsible, the omega-3 fatty acid oil may optionally be used in pharmaceutical compositions, nutritional compositions, dietary supplement compositions, etc., including excipients, carriers, diluents, etc. Includes one or more suitable components. For example, in some embodiments, the ω-3 fatty acid oil is a chemical antioxidant such as α-tocopherol, an oil such as soybean oil or partially hydrogenated vegetable oil, a lubricant such as distillate palm oil, and the like. Containing lecithin, mineral oils or mixtures thereof.

In some embodiments, the ω-3 fatty acid oil is a mixed fatty acid composition comprising LOVAZA® ω-3 fatty acid ester (K85EE, Pronova Biocare, Lysaker, Norway), preferably comprising: (Here, "EE" refers to ethyl ester).

In some embodiments, the ω-3 fatty acid oil is US Pharmacopeia (“USP”), and National Formula, Dietary Supplements (eg, announced November 1, 2008, official date May 1, 2009, USP32-. Described in NF7) and / or Second Supplement (announced June 1, 2009, official date December 1, 2009); The United States Pharmacopoeial Combination; United Book Press It is a fish oil containing ω-3 acid.

In some embodiments, the omega-3 fatty acid oil is obtained from the body oils of fish families such as Anchovy, Carangidae, Clupeidae, Smelt, Scombridae and Scombridae. In some embodiments, the fish oil is purified using, for example, a urea fraction followed by molecular distillation.
In some embodiments, the ω-3 fatty acid oil is 90% by weight or more of the ω-3 fatty acid EPA, DHA, docosapentaenoic acid (“DPA”), including the case obtained from the fish oil described above. Stearidonic acid (“SDA”), eicosapentaenoic acid (“HPA”), eicosatetraenoic acid (“ETA”) and α-linolenic acid (“ALA”), and preferably 80-88% by weight EPA and It contains DHA, 43-49.5% EPA and 34.7-40.3% by weight DHA.

In some embodiments, the omega-3 fatty acid oil is a USP monograph for ω-3 acid ethyl esters (announced June 30, 2009, official date February 1, 2011, USP33-NF28 2nd supplement; It is described in The United States Pharmacopeial Convention (Rockville, MD).

Omega 3 fatty acid oils are present as active ingredients and therefore provide or test for physiological or pharmacological activity or other effects, for example in the diagnosis, cure, alleviation, treatment or prevention of a disease or condition. It is intended to affect the structure or arbitrary function of the body (eg, mammals, especially humans). At least one of the ω-3 fatty acids present in the oil contributes to the activity. It will be appreciated by those skilled in the art that one or more other compositions in the omega-3 fatty acid oil may be partially involved in the activity. It will also be appreciated that different compositions may provide different types and / or levels of activity.

In some embodiments, the omega-3 fatty acid oil is the only active ingredient in the emulsion or pre-emulsion concentrate composition. In some embodiments, the one or more specific ω-3 fatty acids present, and optionally one or more other fatty acids, are the only activity in the emulsion or pre-emulsion concentrate composition. It is an ingredient (s).

Surfactants The emulsions and pre-emulsion concentrate compositions of the present invention further comprise one or more surfactants.

Surfactants are well known in the art and are described, for example, in Handbook of Pharmaceutical Excipients, Rowe, R. et al. C. et al. Please refer to the 5th edition. In a preferred embodiment, the surfactant (either single or in combination) is characterized by one or more of the following characteristics:
a) Miscible (ie producing a single phase) or partially miscible with ω-3 fatty acid oils (when used with or without any co-solvent).
b) Safe for use in pharmaceutical, nutritional or dietary supplement products (eg, approved for use in such products, safely used in such products, and / or classified as GRAS (Safety Certified)). ,
c) It has a peroxide value of <5 and a water content of <2.0, and / or d) has a high HLB (“hydrophilic-lipophilic balance”), eg, an HLB value of 10-18.

In some embodiments, the surfactant comprises one or more nonionic hydrophilic surfactants selected from the following:
a) Polyoxyethylene castor oil derivatives, including those commercially available under the trade name "CREMOPHOR" (BASF, Mount Olive, NJ), particularly
CREMOPHOR EL or ELP (PEG 35 castor oil, polyethoxylated castor oil, macrogoglyceroli ricinoleas), macrogoglyceroli hydroxystearas (macroglycelloli hydroxystearas) CREMOPHOR ELP (low content of water, K and free fatty acids, refined grade of CREMOPHOR EL, polyoxyethylene glycolized castor oil), and CREMOPHOR RH 40 (polyoxyl 40 hydrogenated castor oil, macrogolglycerol). Hydroxystearic acid, polyoxyethylene 40 hydrogenated castor oil, also referred to as PEG-40 hydrogenated castor oil), and b) polyoxyethylene, including those commercially available under the brand name "TWEEN" (ICI Americas). Sorbitane fatty acid esters, especially
TWEEN 80 (80 [polyoxyethylene (20) monooleate sorbitan], also known as polysorbate 80); polyoxyethylene 20 monooleate sorbitan (sorbitol polymerized with ethylene oxide and a partial fatty acid ester of its anhydride). , More specifically polyoxyethylene-sorbitan-fatty acid mono-oleic ester, (including a mixture of fatty acids including myristic acid, palmitic acid, palmitreic acid, stearic acid, oleic acid and linolenic acid, mainly oleic acid),
TWEEN 85 (85 [polyoxyethylene (20) sorbitan trioleate], also known as polysorbate 85); polyoxyethylene 20 sorbitan trioleate (sorbitol polymerized with ethylene oxide and a partial fatty acid ester of its anhydride). , Specifically, polyoxyethylene-sorbitan-fatty acid tri-oleyl ester (including a mixture of myristic acid, palmitic acid, palmitreic acid, stearic acid, oleic acid and linolenic acid, fatty acids including predominantly oleic acid),
TWEEN 20 (polysorbate 20, also known as a poly (oxy-1,2-ethandyl) derivative); polyoxyethylene 20 laurate; polyoxyethylene 20 monolaurate sorbitan, sorbitan monododecanoart;
TWEEN 60 (polysorbate 60, polyoxyethylene 20 stearate (also known as sorbitan monooctadecanoate poly (oxy-1,2-ethandyl) derivative), and TWEEN 40 (polysorbate 40, polyoxyethylene 20 sorbitan monopalmitate). , Also known as sorbitan monohexadecanoart).

In some embodiments, the surfactant is selected from polyoxyethylene castor oil derivatives (particularly CREMOPHOR EL, CREMOPHOR ELP), polyoxyethylene sorbitan fatty acid esters (particularly TWEEN 80), and mixtures thereof. In some more specific embodiments, the detergent component is about 10-20 (eg, about 15) weight% CREMOPHOR EL or ELP, and about 80-90 (eg, about), based on the total surfactant component. 85) Contains TWEEN 80 by weight.

Any component The emulsion or pre-emulsion concentrate composition of the present invention may optionally contain one or more co-solvents. Although not intended to be bound by theory, mechanism or the like, co-solvents can be used to improve the miscibility of, for example, omega-3 fatty acid oils and surfactants. In some embodiments, the co-solvent is premixed with one or more surfactants.

In some embodiments, the cosolvent is selected from water, C _1-4 alcohols (straight or branched chains such as ethanol, "EtOH"), C _12-22 fatty acids (eg oleic acid), and mixtures thereof. Will be done. It has been found that the co-solvent can affect the particle size of the resulting emulsion. For example, oleic acid tends to increase particle size. It is possible to hypothesize that other fatty acids can act in the same way. Ethanol and water did not tend to affect particle size or tended to reduce particle size slightly. It is possible to hypothesize that other alcohols can act in the same way.

The presence of a small amount of water in the pre-emulsion concentrate composition of the invention, especially at equilibrium, tends to improve the clarity and / or miscibility of the omega-3 fatty acid oil and surfactant in the composition. It was surprisingly found. In some embodiments, water is about 0.1 to about 5% by weight, preferably about 0.7 to about 5% by weight, more preferably about 0, based on the total weight of the pre-emulsion concentrate composition. It is present in an amount of 7 to about 1.2% by weight (determined by Karl Fischer titration; appropriate use of equivalent methods including Metrohm 774/756 oven sample processor KF coulometer or volumetric method). Water can be present by direct addition of the preconcentrate to the composition and / or through absorption of water during the production of the composition (eg, from the material or environment used). In some embodiments, water is absorbed during production. For example, water is from the material used to prepare the capsule during the preparation of the pre-encapsulation emulsion concentration, eg from the material used to prepare a soft gelatin capsule (eg, a gelatinous mixture containing gelatin and water). , Can be absorbed. The present invention includes a pre-encapsulation emulsion composition produced by such a process. The preparation of soft gelatin capsules and other capsules is well known in the art. For example, Remington: The Science & Practice of Pharmacy, 20th Edition, Alfonso R. et al. See Gennaro ed., Lippincott Williams & Watkins, 2000, eg 885-891.

The emulsions and pre-emulsion concentrate compositions of the present invention are one or more pharmaceutical agents, veterinary agents, nutritional supplements or nutritional supplements (eg, fragrances, minerals), or colorants (eg, dyes, pigments), preservatives. It can also serve as a carrier or vehicle for any other ingredient, including excipients such as agents and antioxidants.

In some embodiments, the composition of the invention comprises one or more active ingredients other than the omega-3 fatty acid oil. The other active ingredient (s) are contained in a mixture comprising ω-3 fatty acid oil (eg, in the filling component of the capsule, characterized in that the filling comprises a pre-emulsion concentrate composition. Incorporating into at least one component of the capsule shell of the capsule comprising the pre-emulsion concentrate composition into a coating on the capsule comprising the pre-emulsion concentrate composition, or in any combination thereof. ) Can exist.

For example, one or more other active ingredients are substantially dissolved in the composition (eg, in a mixture of ω-3 fatty acid oil, surfactant and any co-solvent, eg, pre-emulsion concentrate composition). To form a substantially homogeneous solution of the active ingredient (s) in the composition. In some embodiments, an essentially homogeneous solution is formed (ie, less than 10% by weight, preferably less than 5% by weight, of the other active ingredient (s), based on the weight of the composition. Preferably 1% by weight remains undissolved). In some embodiments, the active ingredient (s) are completely dissolved.

In other embodiments, some of the at least one or more other active ingredients are in a composition (eg, a mixture of an omega-3 fatty acid oil, a surfactant and any co-solvent, eg, a pre-emulsion concentrate composition). It exists as a suspension in the substance). In some embodiments, the suspension comprises solid crystalline particles, solid amorphous particles, or a mixture thereof of one or more other active ingredients in the composition. In some embodiments, at least about 80-100% of one or more other active ingredients (eg, at least about 80-99%, including at least about 85, 90 or 95%) are in suspension. It exists as a solid particle.

In other embodiments, the one or more other active ingredients are present in one or more coatings on a capsule (eg, a softgel capsule) containing the pre-emulsion concentrate composition. Examples of coatings containing active ingredients that can be used in the present invention include those disclosed in US Published Patent Application US2007 / 0212411A1.

The active ingredient, including different other active ingredients, may be present in any combination of the aforementioned forms. In a preferred embodiment, such compositions of the invention include oral formulations, especially capsules, and most particularly softgel capsules.

Examples of other active ingredients are analgesics, anti-inflammatory agents, anti-corticosteroids, antiarrhythmic agents, anti-asthma agents, antibacterial agents, antiviral agents, anticoagulants, nootropics, antidepressants, antidiabetic agents. , Anti-asthma, anti-fungal, anti-gout, anti-pressurant, anti-malaria, anti-mitral pain, anti-muscleline, anti-neoplastic, immunosuppressive, live antigen, anti-thyroid, anti-cough Agents, anxiety relievers, analgesics, hypnotics, nerve relaxants, neuroprotectants, β-blockers, cardiotonics, cell adhesion inhibitors, corticosteroids, cytokine receptor activity regulators, diuretics, anti-Parkinson agents, Gastrointestinal agents, histamine H receptor antagonists, keratolytic agents, lipid regulators, muscle relaxants, nitrates and other antiarrhythmic agents, non-steroidal antiasthma agents, nutritional agents, opioid analgesics, sex hormones, stimulants Also including, but not limited to, antiarrhythmic agents.

In some embodiments, the other active ingredient (s) are fatty acids other than ω-3 fatty acid oils, sterol fatty acid esters or stanol fatty acid esters, statin compounds, squalane synthesis inhibitors, azetidinone-based cholesterol absorption inhibitors. , LDL (Low Density Lipoprotein) Catalytic Accelerator, Peroxysome Proliferator Responsive Receptor (PPAR) Agonist and / or Agonist, Derivatives such as Niacin and Nicotinic Acid Amid, Bile Acid Blocking Agent, MTP Inhibitor, LXR Agonist And / or antagonists, and combinations thereof, and the like, including, but not limited to, lipid regulators.

Specific examples of other active ingredients include the drug substance disclosed in US Published Patent Application US2007 / 0212411A1 described above.

Emulsion and Pre-Emulsion Concentrate Composition of the Invention The relative proportions of the components in the composition of the invention are formed, for example, from the particular type of composition considered, eg, it is a pre-emulsion concentrate, emulsion, emulsion. Even oral formulations) and will vary depending on the particular ingredient used. Determination of a viable ratio in any particular embodiment will generally be within the ability of one of ordinary skill in the art in the light of the present disclosure. All indicated ratios and relative weight ranges described herein are therefore understood to represent only preferred or more specific teachings and are not intended to limit the invention in its broadest sense. ..

Pre-Emulsion Concentrate Composition In some embodiments, the pre-emulsion concentrate composition of the present invention is:
About 60 to about 85% by weight (eg, about 60 to about 80% by weight, for example about 70% by weight) of ω-3 fatty acid oil and about 15 to about 40% by weight (for example, about 20 to about 40% by weight (for example, about 70% by weight)). 30% by weight) and containing a surfactant
0 to about 5% by weight (eg, about 0.1 to about 5% by weight, or about 0.7 to about 5% by weight, or about 0.7 to about 1) based on the total weight of the pre-emulsion concentrate composition. .2% by weight) co-solvent can optionally be further included.

For example, the pre-emulsion concentrate composition of the present invention is
Based on the weight of the omega-3 fatty acid oil and surfactant in the pre-emulsion concentrate composition,
About 60-80% by weight of ω-3 fatty acid oil,
Approximately 20-40% by weight surfactant and optionally
Based on the total weight of the pre-emulsion concentrate composition, it can contain from about 0.7 to about 5% by weight (eg, about 0.7 to about 1.2% by weight) of co-solvent.
Or in some embodiments
Based on the weight of the omega-3 fatty acid oil and surfactant in the pre-emulsion concentrate composition,
About 70% by weight of ω-3 fatty acid oil and
Based on about 30% by weight of surfactant and optionally the total weight of the pre-emulsion concentrate composition,
It can contain from about 0.7 to about 5% by weight (eg, about 0.7 to about 1.2% by weight) of co-solvent.

In some embodiments, the weight ratio of the omega-3 fatty acid oil to the surfactant in the composition is greater than 2: 1 (eg 2: 1 to about 6: 1 or 2: 1 to about 4: 1). range).

As mentioned above, the pre-emulsion concentrate or emulsion can consist of one or more omega-3 fatty acid oils, surfactants, and / and co-solvents. In some embodiments of the pre-emulsion concentrate composition described above, the ω-3 fatty acid oil is K85EE and the surfactants are polyoxyethylene castor oil derivatives (particularly CREMOPHOR EL, CREMOPHOR ELP), polyoxyethylene sorbitan. Selected from fatty acid esters (particularly TWEEN 80), and mixtures thereof, any co-solvent is water. In one embodiment of such composition, the detergent components are about 10-20 (eg, about 15) weight% CREMOPHOR EL or ELP, and about 80-90 (eg, about 80-90), based on the total surfactant component. Approximately 85) Contains TWEEN 80 by weight.

The pre-concentrate of the present invention can be formed by combining the omega-3 fatty acid oil and the surfactant components and mixing until the combination is uniform. Generally, the surfactant is warmed (eg to about 30 ° C.) and liquefied in solid or semi-solid form and then mixed with the omega-3 fatty acid oil. Any component can be mixed in combination with a separate component or a mixture of components.

In some embodiments, the pre-emulsion concentrate of the present invention comprises a step of combining the surfactant (s) with a co-solvent (eg, water), a step of mixing until the combination is uniform, and then. It is formed by a process comprising combining the mixture with the ω-3 fatty acid oil (eg, adding the mixture to the oil) and then mixing the combination until uniform. In such embodiments, when the surfactant (s) are in solid or semi-solid form, the surfactant is first heated (eg, to about 30 ° C.) to liquefy the surfactant (s). , Then combine with the co-solvent and mix.

In some embodiments, the invention comprises a hard capsule or a soft capsule, the filling comprising the pre-emulsion concentrate of the invention. The manufacture of hard capsules or soft capsules is generally known to those of skill in the art. For example, soft capsules can be manufactured by a variety of processes, including plate processes, rotary dies, reciprocating dies, and continuous processes. For example, Remington: The Science & Practice of Pharmacy, 20th Edition, Alfonso R. et al. Ed. See "physical products of soft capsules", Pharmaceutical Capsules, 2nd Edition, Pharmaceutical Press, 201-212. See also US Pat. No. 5,478,508 and US Pat. No. 5,882,680, as well as methods for producing seamless capsules disclosed in US Patent Application US2005 / 0106233A1 and US Patent Application US2007 / 0259097A1. I want to be. Capsule materials such as those known in the art can be utilized, examples of capsule materials include natural or synthetic gelatin, pectin, casein, collagen, protein, modified starch, polyvinylpyrrolidone, acrylic polymers, cellulose derivatives ( For example, hydroxypropylmethylcellulose (HPMC), methylcellulose (MC)), arginate and other polysaccharides, and combinations thereof are optionally included with one or more plasticizers and / or water. Capsule material can further include one or more preservatives, colorants, opalescents, flavoring agents, sweeteners, sugars, gastric resistant substances or combinations thereof. In a currently preferred embodiment, the capsule is a soft gelatin capsule (“softgel cap” or “softgel capsule”).

The shape and size of the capsule can vary according to the present invention. The shape of the capsule is spherical or circular, oval, tubular, oval, twisted, or non-standard (eg, fish, tree, star, heart, or bear), preferably oval, to these. Not limited. The size of the capsule used will vary according to the volume of the filling composition intended to be contained therein.

For example, in some embodiments of the invention, hard gelatin capsules or soft gelatin capsules can be produced according to conventional methods as a single unit containing standard capsule shapes. A single soft gelatin capsule can be supplied in an oval, oval or other shape, typically in a size of, for example, 3 to 22 minim (1 minimim equals 0.0616 ml). .. Gelatin capsules are customarily described as, for example, (000), (00), (0), (1), (2), (3), (4) and (5) according to conventional methods. It can also be typically manufactured as sealed or unsealed two-piece hard gelatin capsules of standard shape and various standard sizes. The largest number refers to the smallest size. Non-standard shapes can be used as well.

For example, pre-emulsion concentrate capsules are suitably formed into soft gelatin capsules by direct encapsulation of a mixture containing ω-3 fatty acid oil and a surfactant. In the compounding process, the oil and surfactant were blended. Continuous mixing is applied or / or an additional about 1% by weight of water is added to the mixture to assist in the formation of, for example, homogeneous solutions. Appropriate selection of equipment and conditions minimizes the risk of oxidation, eliminates foaming or bubbling, and is suitable, for example, a nitrogen atmosphere generator, a sealed mixing tank with recirculation and vacuum capacity. The mixture is then encapsulated appropriately using a rotary encapsulation method. For the formation of capsules, a molten gel mass (eg, containing gelatin, glycerol and water) is machine cast into two continuous ribbons, leading to a converging part between a pair of dies and an infusion wedge, through which. And pump the filling mixture in a fixed amount. Capsule filling and sealing occur essentially simultaneously, forming capsules of the desired size, shell weight, filling weight and sealing thickness. Capsules are first tumbler dried in a rotary dryer (eg, 15 minutes / segment for a total of about 60-75 minutes) and then dried in a shallow tray by a tunnel dryer to achieve suitable hardness (eg, by tunnel dryer). For example, dried to at least 8.5 Newton). The capsules are properly ground or spray washed, for example with isopropyl alcohol, to remove the lubricant used during the process.

In some embodiments, the capsules of the invention are one or more coatings, including coatings such as coatings and / or binders, and optionally other conventional additives known in the art. Can be coated with. The coating (s) can be applied, for example, as a solution, suspension, spray, dust or powder by any conventional technique such as pan coating, fluidized bed coating or spray coating. The coating (s) can be formulated for immediate release, delayed release, intestinal release, sustained release, protective coating, hermetic coating, and / or barrier coating according to methods well known in the art. Conventional coating techniques include, for example, Remington: The Science & Practice of Pharmacy, 20th Edition, Alfonso R. et al. Ed., Gennarro, Lippincott Williams & Watkins, 2000, eg, 894-902. Examples of coating film forming materials and conventional additives include those disclosed in US Patent Application US2007 / 0212411A1, US Patent Application US2005 / 0106233A1 and US Patent Application US2007 / 0259097A1. As discussed above, one or more coatings can contain one or more other active ingredients.

When the pre-emulsion concentrate of the invention is orally administered, the emulsion can be formed upon contact with aqueous gastric fluid with or without co-administration with a suitable aqueous liquid. The pre-emulsion concentrate of the invention can also be diluted with a suitable aqueous solution prior to administration (in some embodiments forming an emulsion), which is then administered. Suitable aqueous liquids are edible and include water itself, juice, or other beverage or drinking liquid containing water. The emulsion formed can have any of the features of the emulsion described herein (eg, a central particle size of about 100 nm to about 3 μm).

Emulsion Composition In some embodiments, the emulsion composition of the present invention is:
About 15 to about 30% by weight of ω-3 fatty acid oil,
With about 5 to about 10% by weight of surfactant,
Aqueous liquids that provide about 65-80% by weight of water,
Optionally containing from about 0 to about 5% by weight of co-solvent (other than water),
The weight percentage is based on the total weight of the emulsion composition.

In some of these embodiments, the ω-3 fatty acid oil is K85EE and the surfactant is a polyoxyethylene castor oil derivative (particularly CREMOPHOR EL, CREMOPHOR ELP), a polyoxyethylene sorbitan fatty acid ester (particularly TWEEN 80). And their mixtures, any co-solvent is selected from C _12-22 fatty acids (particularly oleic acid), C _1-4 alcohols (especially ethanol) and mixtures thereof.

Suitable aqueous liquids are edible and include water itself, juice, or other beverage or drinking liquid containing water. It will be understood that proper water is needed to obtain the emulsion. Generally, the emulsion composition will contain at least about 70% by weight of water, based on the weight of the composition.

The emulsion compositions of the present invention are formed in any order by combining ω-3 fatty acid oils, surfactants and aqueous liquid components, and any components, and mixing until uniform. be able to. In other embodiments, the emulsion composition can be formed by mixing the preemulsion concentrate of the invention with an aqueous liquid (eg, including at least about 1% by weight of the preconcentrate).

Use ω-3 Another embodiment of the invention in which an omega 3 fatty acid oil can be used is the manufacture of a pharmaceutical product (or pharmaceutical product) nutritional product, a dietary supplement product suitable for the treatment of any of a disease, condition or the same kind. Provided is the use of an emulsion of the present invention or a composition of a preconcentrate of an emulsion for the purpose.

Another embodiment of the invention in which an omega-3 fatty acid oil can be used is an emulsion or pre-emulsion concentrate composition of the invention (diluted version thereof) for the treatment of any disease, pathology or the like. Provided is a therapeutic method comprising administering (including) to a subject in need thereof.

As used herein, "treating" with respect to a disease or condition includes: (1) ameliorating or preventing a disease or condition, or one or more biological signs of a disease or condition, (2) (a) one in a biological cascade linked to or involved in the disease or condition. Or to prevent multiple points or (b) one or more biological signs of a disease or condition, (3) alleviate one or more symptoms or effects associated with a disease or condition, or (4). ) Delaying the transition of a disease or condition, or one or more biological signs of a disease or condition.

As mentioned above, "treatment" of a disease or condition includes prevention of the disease or condition. Those skilled in the art will recognize that "prevention" is not an absolute term. In medicine, "prevention" is a drug or activity that substantially reduces the likelihood or severity of a disease or condition or its biological signs, or delays the onset of such disease or condition or its biological signs. It is understood to refer to the prophylactic administration of the ingredient. Therefore, prevention involves reducing the risk of developing a disease or condition.

As used herein, "subject" refers to a human or other animal (eg, a mammal).

Emulsions or pre-emulsion concentrate compositions are generally administered in safe and effective amounts. That is, an amount sufficient to treat the subject's disease or condition, but low enough to avoid serious side effects (with reasonable benefit / risk ratio) within reasonable medical judgment. be. A safe and effective amount is the particular composition chosen (eg, taking into account the efficacy, efficacy and half-life of the active ingredient); the route of administration chosen; the disease or condition being treated; Severity of the disease or condition being treated; age, size, weight and physical condition of the subject being treated; medical history of the subject to be treated; duration of treatment; nature of combination therapy; desired therapeutic effect; and Similar factors will vary depending on what can be customarily determined by those skilled in the art.

Diseases or conditions in which an omega-3 fatty acid oil can be used include diseases or conditions in which one or more compositions of ω-3 fatty acids can be used. Examples of diseases or conditions in which omega-3 fatty acids (s) and omega-3 fatty acid oils can be used include novel uses that can be identified as well as those currently known, and one or more abnormal plasma lipids. Includes treatment of levels or abnormal cardiovascular function. For example, ω-3 fatty acid oils are hypertriglyceridemia, hypercholesterolemia, mixed dyslipidemia, cardiovascular disease, coronary heart disease (CHD), vascular disease, atherosclerotic disease and related. For the treatment of at least one condition or disease, independently selected from the group consisting of the pathological conditions, and / or for the prevention or reduction of cardiovascular and / or vascular events (including MACE, MCE). , Can be used. The disease or condition can be any of those disclosed in US Pat. No. 5,502,077, US Pat. No. 5,656,667 or US Pat. No. 5,698,594.

Cardiovascular disease (CVD) is a broad term that includes a variety of diseases and conditions. The term refers to any disorder in any of the various parts of the cardiovascular system consisting of all blood vessels found throughout the heart and body. Cardiac disorders can include coronary artery disease, CHD, myocardial disease, valvular heart disease, pericardial disease, congenital heart disease (eg, stenosis, atrial septal defect or ventricular septal defect) and heart failure. Vascular disorders include arteriosclerosis, atherosclerosis, hypertension, stroke, vascular dementia, aneurysms, peripheral arterial disease, intermittent lameness, vasculitis, venous valvular insufficiency, venous thrombosis, dilated serpentine. May include venous and lymphatic edema. Some patients can receive treatment for CVD, such as reconstruction of blood vessels or coronary arteries (angioplasty with or without stenting, or angiografts). Although some types of cardiovascular disease are congenital, many are acquired after middle age and are due to deskwork-centric lifestyles and unhealthy habits such as smoking. Some types of CVD include angina such as myocardial infarction (MI) or coronary intervention, major adverse cardiovascular events (MACE) and / or major coronary events (MCE), or possibly death (cardiac death or It may also lead to further cardiac disorders such as cardiovascular death), emphasizing the importance of CVD treatment and prevention efforts.

Omega 3 fatty acid oils can be used for primary or secondary prophylaxis. Primary preventive efforts focus on reducing known risk factors for CVD, or preventing their occurrence, with the aim of delaying or preventing the initiation of CVD, MACE or MCE. Secondary preventive efforts focus on reduced recurrent CVD and reduced risk of death, MACE or MCE in patients with existing CVD.

MACE includes cardiac death, other cardiovascular death, MCE (myocardial infarction (MI), and coronary artery reconstruction, angiogenesis, percutaneous transluminal coronary angioplasty (PTCA), percutaneous coronary intervention (PCI) and coronary bypass grafts (PCE). Includes coronary interventions such as CABG), hospitalization for unstable angina, stroke, transient ischemic attack (TIA) and hospitalization for peripheral arterial disease (PAD).

CHD includes MI and stable angina (or unstable angina), myocardial ischemia demonstrated by non-invasive examination, and symptomatic ischemic heart disease including a history of coronary artery procedures (eg NCEP). See ATP III).

The invention includes the use of the compositions of the invention to treat any of the aforementioned diseases or conditions.

In some embodiments, an emulsion or pre-emulsion concentrate composition is used to reduce triglyceride (TG). Therefore, in some embodiments, the treatment administers the composition of the invention to reduce TG (eg, very high triglyceride (> 500 mg / dL) or high triglyceride (≧ 200 mg / dL) or border. Includes reducing triglycerides in patients with high triglycerides (150-199 mg / dL) in the line). For example, triglyceride levels in patients with very high triglycerides can be reduced to high levels, borderline high levels, or normal levels; or triglyceride levels in patients with high triglycerides are borderline. Triglyceride levels in patients with high borderline triglycerides can be reduced to normal levels (<150 mg / dL).

In some embodiments, treatment comprises administering the pre-emulsion concentrate or composition of the emulsion of the invention to improve one or more other lipid parameters. In some embodiments, HDL-C (high density lipoprotein cholesterol) is increased and / or non-HDL-C (non-low density lipoprotein cholesterol), LDL-C (low density lipoprotein cholesterol), TC ( Total cholesterol), VLDL-C (ultra-low density lipoprotein cholesterol), TC: HDL-C ratio, and one or more lipid parameters of ApoB (apolipoprotein B) are reduced. In some embodiments, treatment comprises administering the composition of the invention to reduce TG and further ameliorate one or more of the other lipid parameters described above. ..

For example, in some embodiments, non-HDL-C is reduced, or both non-HDL-C and TG are reduced. In some embodiments, non-HDL-C and TG are reduced in patients with mixed dyslipidemia with high TG. Such patients can receive parallel therapy (eg, statin therapy).

In some embodiments, the treatment is to administer the composition of the invention to improve postprandial lipid parameters, eg, increase postprandial HDL, and / or one or more meals. Includes subsequent reduction of TG, non-HDL-C, LDL-C, TC, VLDL-C, TC: HDL ratios and ApoB levels.

In some embodiments, TG is reduced to at least about 5% (eg, at least about 10, 15, 20, 25, 30, 40 or 60%) after treatment (compared to pretreatment baseline TG values). Will be done. In some embodiments, the reduction in TG after treatment with the compositions of the invention exceeds any reduction in TG after treatment with a non-emulsifying omega-3 fatty acid oil administered at an equivalent or higher actual dose. For example, a reduction in TG of at least about 5%, 10%, and more than 15% (compared to the baseline TG value before treatment, respectively).

In some embodiments, improvements in one or more other lipid parameters after treatment with the compositions of the invention are post-treatment with a non-emulsifying omega-3 fatty acid oil administered at an equivalent or higher actual dose. Beyond any improvement in. (Each increases or decreases as prescribed compared to pretreatment baseline lipid levels (s)).

In some embodiments, improvements in TG or other lipid parameters (s) use equivalent or lower doses of omega-3 fatty acid oil compared to the dose of non-emulsified omega-3 fatty acid oil. Will be achieved.

In some embodiments, improvements in TG or other lipid parameters (s) are achieved by treatment during 4 weeks, 8 weeks, 12 weeks, 24 weeks or 1 year.

Other embodiments of the invention include oral administration of the emulsion or pre-emulsion concentrate composition of the invention to a subject, where oral absorption and / or oral bioavailability is used in the composition. Oral absorption (exposure) and / or oral absorption (exposure) of ω-3 fatty acids in subjects requiring treatment with ω-3 fatty acids, which is increased compared to oral absorption and / or oral bioavailability after administration of -3 fatty acid oils. Alternatively, a method for increasing oral bioavailability is provided.

In some embodiments, the increase in absorption is indicated by an increase in the measured total omega-3 fatty acid in AUC. In some embodiments, the measured ω-3 fatty acid is EPA and / or DHA. In some embodiments, serum levels of total EPA and / or DHA are increased, preferably serum levels of total EPA and / or DHA are total after administration of the omega-3 fatty acid oil used in the composition. It is increased by at least about 2, 3 or 4 times (eg, at least about 2 times to about 5 to 15 times) compared to serum levels of EPA and / or DHA. In some embodiments, serum levels of free EPA and / or DHA are also increased compared to serum levels of free EPA and / or DHA after administration of the omega-3 fatty acid oil used in the composition. ..

The emulsions and pre-emulsion concentrate compositions of the present invention can be used for administration in any suitable manner. In a preferred embodiment, the composition is a unit formulation, such as, for example, in the form of a hard capsule or a soft capsule (including a gelatin capsule); or an emulsion or pre-emulsion concentrate composition of the invention to form a drinking mixture containing a beverage. It is orally administered in a drinking form such as an edible liquid formed by mixing with other components (such as the aqueous liquid described herein). In a preferred embodiment, the pre-emulsion concentrate composition is administered in an encapsulated form, particularly as a soft gelatin capsule.

The pre-emulsion concentrate or composition of the emulsion is administered in an amount and frequency that provides the desired treatment. Generally, the composition of the pre-concentrate or emulsion is, for example, about 0.1 g to about 10 g, about 0.5 g to about 8 g, about 0.75 g to about 4 g, about 0.1 g to about 2 g, about per day. About 0.1 g, 0.5 g, 0.75 g or about 1 g, ~ about 1 g, 1.5 g, 2 g, 3 g, 4 g, 8 g, or 10 g per day, including 0.5 g to about 1.5 g or about 1 g. Is administered to provide a daily dose of ω-3 fatty acid oil (preferably a daily dose of ω-3 fatty acid). In some embodiments, administration is to provide about 1-4 g (particularly including about 1, 2, 3 or 4 g) of ω-3 fatty acid oil (preferably ω-3 fatty acid) per day. ..

A daily dose of omega-3 fatty acid oil will be administered at a dose of 1-10 (eg, a dose of 1-4 or 1-2 per day). For example, one or two capsules can be administered twice daily (ie, 2 or 4 capsules per day) to provide the desired total daily dose.

The pre-emulsion concentrate or composition can be administered over a period sufficient to provide and maintain the desired treatment. Generally, the compositions of the invention will be administered for at least 4 weeks, including at least 8 weeks, 12 weeks or 24 weeks or at least 1 year.

In some embodiments, the pre-emulsion concentrate composition of the present invention is orally administered with a suitable aqueous liquid (water itself, juice or other beverage containing water or an edible liquid containing a drinking liquid). For example, the pre-emulsion concentrate composition can be administered with up to about 500 ml of a suitable aqueous liquid.

The therapeutic methods of the invention are monotherapy, or one or more therapeutic agents or therapies, using, for example, one or more of the active ingredients disclosed above, which can be administered in effective amounts. It can be achieved by using the pre-emulsion concentrate or composition of the emulsion of the present invention in double or multiple combination therapies with. One or more compounds from a given class or different classes can be used in combination with the pre-emulsion concentrate or composition of the emulsion of the present invention. Use in combination includes not only regimens but also combination products (eg, formulations including those described above herein). Thus, the active ingredient (s) can be a single pre-emulsion concentrate or different compositions that can be combined into the composition of the emulsion or administered to the patient simultaneously or at different times.

In some embodiments, the therapeutic method of the invention is achieved using a pre-emulsion concentrate or composition of an emulsion as a monotherapy in which the omega-3 fatty acid oil is the only active ingredient (as described above). Will be done.

In other embodiments, the therapeutic methods of the invention can be used in effective amounts (eg, in prescription information), including amounts known in the art, at least one as described herein. Achieved by combination therapy with two other active ingredients (eg, lipid regulators). In certain embodiments, the at least one other lipid active ingredient comprises a statin.

Example 1-Method of determining particle size (including median and x90)
Formed from a pre-concentrate using a Malvern particle size analyzer (Mastersizer 2000 version 5.40; Malvern Instruments, Westborough, MA, USA) or equivalent, which measures particle size using static laser light scattering techniques. Determine the particle size of the emulsion containing the emulsion to be made.

For example, the pre-emulsion concentrate of the present invention is combined with deionized water at room temperature (about 25 ° C.) at a ratio of 1 g of pre-concentrate to 20 ml of water. The mixture is tilted 20 turns (eg, in a test tube, by hand, causing foaming or foaming, so be careful not to shake) to disperse the components to form an emulsion. The particle size distribution (frequency vs. particle diameter based on normalized volume distribution) is determined by Mastersizer 2000 and is sometimes referred to as the median and other particle size statistics (50th percentile of cumulative size distribution, D50). ) And x90 (90th percentile value of the cumulative size distribution, sometimes referred to as D90). Water was used as the medium in the Mastersizer. The median and x90 particle size of other emulsion compositions of the invention (eg, test liquid emulsions) are also determined using Mastersizer 2000, using the test composition directly.

Example 2-Method for determining relative bioavailability Following feeding, digestion and absorption of ω-3 fatty acids from ω-3 fatty acid esters comprises three different steps: Hydrolysis of ω-3 fatty acids from bound alcohol, absorption / transport into intestinal cells of the intestine, and subsequent packaging for intestinal use or transport to the body (understood by those skilled in the art). As such, digestion and absorption following the intake of the corresponding free fatty acid will include the last two steps).

After rapid and complete hydrolysis of the ω-3 ethyl ester by esterase in the intestine, the free fatty acids are absorbed / transported into the intestinal enterocytes, rapidly re-esterified, and systemically circulated via the thoracic duct as chylomicrons. come in. Following passage through the thoracic duct, chylomicrons enter plasma. The normal half-life of chylomicrons in circulation is about 10 minutes. Lipoprotein lipase, present on the endothelial surface of the capillary bed, hydrolyzes the chylomicron triglyceride core and releases fatty acids for tissue uptake.

Absorption of ω-3 fatty acids into the systemic circulation can be measured directly after release of the free fatty acid forms from their esterified form (chylomicrons) by determining plasma levels and total levels of those free forms.

In addition, the fatty acid composition of serum phospholipids correlates with levels incorporated into membranes (eg, erythrocyte membranes, monocytic membranes and platelet membranes) (eg Katan, MB, et al., J Lipid Res. 1997; 38). : 2012-22 and Tremoli, E et al., Am J Clin Nutr. 1995; 67: 607-13). The ω-3 fatty acid composition of the erythrocyte and platelet membranes also correlates with the systemic content of these compounds. Therefore, analysis of blood phospholipids is an appropriate way to assess the performance of products intended to increase the systemic accumulation of omega-3 fatty acids. Analysis of plasma phospholipids can be performed, for example, by Harris, W. et al. et al. Clinical Biochemistry 43 (2010) 338-340; Harris, W. et al. et al. , American Journal of Clinical Nutrition 2007; 86: 1621-5; Cao, J. Mol. et al. , Clinical Chemistry 52: 12 2265-2271 (2006); Harris, W. et al. et al. , Preventive Medicine 39 (2004) 212-220; and Park, Y. et al. et al. , Journal of Lipid Research 44, 2003 455-463.

Therefore, when examining the absorption of ω-3 fatty acids, including EPA and DHA (eg, from ω-3-acid ethyl esters, including ethyl esters of EPA and DHA), EPA and DHA in plasma or serum phospholipids. The increase can be used as a measure of absorption. These absorption measurements can be used as oral bioavailability measurements.

The methodology for measuring the absorption of ω-3 fatty acids will be described in more detail in the following experiments (s). The following definitions can be used herein.
Cmax-Maximum observed concentration AUC-Concentration-Area under the time curve AUC _(0-x) -AUCAUC _(0-t) from zero (pre-dose) time to a fixed reference time-in-subject over all treatments AUC from zero (pre-dose) to final time of quantifiable concentration
AUC _(0-∞) -Estimated AUC from zero (pre-dose) time to infinite time
Time of appearance of Tmax-Cmax t1 / 2-final phase half-life CV-coefficient of variation (CVb = between subjects; CVw = within the subject)
CI-Confidence Interval LS-Least Squares Other statistical terms are used explicitly or contextually in line with commonly used meanings, unless otherwise indicated.

Example 3-Relative Bioavailability Study In two separate studies in dogs, the relative bioavailability of 100% K85EE oil was compared to seven K85EE oil emulsion formulations (5 pre-concentrate capsules and). Two liquid formulations). Each formulation was fasted as a single oral dose (by gavage for liquid formulations) at target doses of 26.8 and 20.5 mg / kg EPA and DHA ethyl esters (EE). I gave each to the Beagle dogs.

Untreated male Beagle dogs (weighing about 9-13 kg) were used in the study. Sampling was performed under fasting conditions with a sampling cycle of 8 hours. That is, the dogs were fasted overnight before each study day and food (standard canine animal feed) was returned to the dogs after an 8-hour blood sampling period. Filtered tap water was freely available.

For pharmacokinetic analysis, at 0, 0.5, 1, 2, 4, 6 and 8 hours post-dose (or at any time similar to the time of dosing, if no dosing) relative to the blood sample Collected. Mix the sampling tube gently and place on ice mixed with water after sampling. Plasma samples were prepared by centrifugation within 1 hour of collection, dispensed into polypropylene tubes and immediately frozen until free and analysis of total EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid).

Plasma was analyzed for total EPA and DHA using a method based on triglyceride digestion, including acidic and basic digestion, followed by liquid-liquid extraction with hexane. Chromatograph separation and detection was performed by an ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC / MS / MS) system with a lower limit of quantification (LLQ) of 0.5 μg / mL. Plasma samples were also analyzed for free EPA and DHA (without triglyceride digestion) using liquid-liquid extraction followed by UHPLC / MS / MS with 0.05 μg / mL LLQ. To take into account the endogenous levels of EPA and DHA, the plasma concentration data was corrected by subtracting the pre-dose values for EPA and DHA to obtain a corrected C _max (C _{max corr} ), which was 8 to the pre-dose plasma concentration. Over time and then subtracted from AUC _0-8 to obtain a corrected AUC _0-8 (AUC _{0-8 corr} ) value. The total concentration minus the free concentration is assumed to be a function of the concentration of circulating EPA or DHA within the chylomicrons that is incorporated ("bound") into the chylomicrons in the systemic circulation.

Study A
Test prescription

Formulation 2 was prepared by mixing Cremophor ELP with K85EE oil until uniform and then adding the mixture to water under mixing.

Either K85EE oil or Liquid Emulsion Formulation 2 was administered to the dogs. (Crossover design with a 2-week washout period between n = 8 / group dosing; n = 4 / group on each treatment day).

On day 1 of the study, blood samples will be taken in fasted dogs over the course of 8 hours without a prescription to administer. On day 2 of the study, reference and emulsion formulations were administered to each of the 4 dogs by oral gavage and the dosing tube was rinsed with approximately 10 ml of water. On the third day of the study, another blank profile is taken, as was done on the first day. After another week (washout), a crossover was performed on the 4th day of the study.

The average doses of EPA and DHA initially administered were 29.6 and 22.7 mg / kg for K85EE and 30.2 and 23.0 mg / kg for Pharmaceutical 2; the average doses subsequently administered. The crossover doses were 29.4 and 22.5 mg / kg for K85EE and 30.0 and 22.8 mg / kg for Pharmaceutical 2.

Both free EPA and DHA and bound EPA and DHA are determined for each sample. Plasma is produced from each sample by centrifugation and frozen until analysis. Take two aliquots for analysis. Alicoat A is analyzed for free EPA and DHA. Aliquot B performs a digestion procedure using alkaline hydrolysis to digest any present TAG circulating in the blood within chylomicrons, followed by analysis of released EPA and DHA.

Freeze-dried powder human serum albumin (Sigma), essentially free of approximately 99% fatty acids (by agarose gel electrophoresis), was used in the assay as an alternative matrix for the analysis of total EPA / DHA and free EPA / DHA. bottom. Due to the levels of endogenous fatty acids in canine plasma, this matrix was validated as a suitable alternative for the preparation of standard and quality control (QC) samples. QC samples prepared at three different sample concentrations and stored with study samples were analyzed with each batch of samples against individually prepared calibration standards. For acceptable analysis, QC results greater than 1/3 must not deviate by more than 15% from the reference concentration and at least 50% of the results from each QC concentration must not be within 15% of the reference concentration. Must not be.

The extraction method was modified for compatibility with the UHPLC-MS / MS system, S. A. Largerstead et al. , Molecular Genetics and Metabolism 73, 38-45 (2001).

For extraction of free DHA and EPA, 50 μL of test sample (human plasma, 25 μL), standard or QC sample is subdivided into vials / tubes. 50 μL of acetonitrile is added to the double blank and 50 μL of the internal standard working solution (500 ng / mL deuterated EPA and DHA) is added to all other vials / tubes. The sample is acidified and then extracted with hexane. After mixing, the supernatant is transferred to a plate containing a silanized glass insert, evaporated under _N2 at 40 ° C. and reconstituted with 50/50 acetonitrile / water. Analysis for free EPA and DHA can then be performed using UHPLC-MS / MS.

For extraction of total DHA and EPA, 50 μL of test sample (human plasma, 25 μL), standard or QC sample is subdivided into micronic vials / tubes. 100 μL of acetonitrile is added to the double blank and 100 μL of the internal standard working solution (500 ng / mL deuterated EPA and DHA) is added to all other vials / tubes. Initial digestion involves the addition of 90/10 acetonitrile / 6N HCl for all samples. Plates are sealed and mixed, followed by incubation at about 104 ° C. for about 45 minutes. After cooling to room temperature, 90/10 methanol / 10N NaOH is added to all wells, the plates are capped, mixed and then incubated as above. After cooling to room temperature, the plates are mixed, centrifuged and 200 μL of supernatant transferred to a clean plate. 6N HCl Then add hexane to all wells. Cap the plate, mix for about 5 minutes, then centrifuge. The supernatant is transferred to a plate containing a silanized glass insert and evaporated under N ₂ at 40 ° C. Samples are reconstituted with 50/50 acetonitrile / water, mixed, centrifuged and then analyzed for all EPA and DHA.

LC separation can be performed in less than 1.5 minutes using an Accuracy UPLC BEH C18, 50 × 2.1 mm, 1.7 μm column with gradient conditions. Alternatively, an equivalent UHPLC device can be used and the chromatographic conditions can be changed slightly.

Plasma concentration vs. time profile: 1) free EPA and DHA from aliquot A; 2) bound EPA and DHA from aliquot B; 3) subtotal of EPA + DHA in TAG from aliquot B and 4) total liberation Produces for EPA and DHA + bound EPA and DHA. AUC (0-t), Cmax and Tmax are calculated for each of the four conditions per animal per formulation. The relative bioavailability (“F”) can be calculated for each test prescription as follows.
F = AUC (0-t) test formulation / AUC (0-t) reference formulation Results are shown in Table 1.

Table 1

After administration of Emulsion Formula 2, the C _{max corr} and AUC _{0-8 corr} values for all EPA and DHA exceeded at least 3 or 4 times these values for K85EE. Corresponding values for free EPA and DHA were also increased compared to K85EE. These data provide evidence of enhanced bioabsorption and bioavailability of Emulsion Formula 2 for EPA and DHA compared to K85EE.

Study B
In the second study, six formulations of K85EE (five preconcentrated capsules and one liquid (by forced dose)) were administered to dogs (n = 4 / group). The study was conducted on 6 separate study days.
Test prescription:

Formulations 3-6 and 8 were prepared by adding a surfactant (s) to the K85EE oil (s) under mixing (magnetic stirrer). When Cremophor ELP was used, it was heated to 30 ° C. before being added to the oil. The mixture was filled into hard gelatin capsules using a pipette.

Formulation 7 was prepared by mixing the surfactant with K85EE oil until uniform and then adding the mixture to water under mixing. When Cremophor ELP was used, it was heated to 30 ° C. to melt and mixed with other components as needed.

Free and total EPA and DHA were analyzed in the manner described above. Pharmacokinetics of free and total EPA and DHA plasma concentrations-time data using a non-compartmental method to obtain PK parameter estimates where possible after appropriate baseline correction of endogenous EPA and DHA. PK) Analysis was performed. The relative bioavailability (“F”) is calculated as follows.
F = AUC _(0-8) test prescription / AUC _(0-8) reference prescription.

Mean C _{max corr} and mean AUC _{0-8 corr} values were compared with K85EE oil (formulation 1) data from Study A and expressed similarly as a ratio. The results are shown in Table 2.

Table 2

After administration of emulsion formulation 3, 4, 5 or 7 (having a central particle size of 130 nm to 1.8 μm as shown), the total AUC _{0-8 corr} value for EPA and DHA is at least this value of K85EE. At least twice or more than three times. Corresponding values for free EPA and DHA were also increased compared to K85EE. Formulation 6 (central particle size 6.3 μm) showed little or no increase in total Cmax _{0-8 corr} and AUC _{0-8 corr} values for EPA and DHA compared to K85EE. Formulation 8 (central particle size 12.8 μm) showed reduced exposure (C _{max corr} and AUC _{0-8 corr} values for both total and free EPA and DHA) compared to K85EE.

Example 4-Clinical Study Relative Bioavailability of EPA and DHA in Plasma After Oral Administration of K85EE Liquid Emulsion and / or Pre-Emulsion Concentrate Capsules Compared to Commercially Available K85EE (eg LOVAZA® Capsules) Studies were conducted to assess the increase in rate and any dose correlation in the uptake of EPA and DHA into phospholipids after repeated administration by emulsion.

Part A included a single dose dose of the equivalent to 1.68 g of LOVAZA® in a pre-emulsion concentrate capsule or liquid emulsion. Part B included a two-week repetitive dose of selected doses of pre-emulsion concentrate capsules.

The primary endpoints were: For Part A, free after a single dose and AUC _(0-∞) and Cmax (corrected from baseline) for total EPA and DHA; for Part B, both EPA and DHA (total and free; baseline). AUC _(0-24h) and Cmax _ss ; and uptake of EPA and DHA into plasma phospholipids (absolute% change from baseline).

More specifically, Part A is a liquid emulsion formulation prepared from commercially available LOVAZA® capsules and pre-concentrate capsules with a single dose of relative bioavailability of the encapsulated K85EE pre-emulsion concentrate. It was an open-label, randomized, parallel-group study in healthy adult subjects compared to the product. Sixteen healthy subjects who met the eligibility criteria were randomized to each of the three parallel treatment groups (with the goal of completing the study with at least 12 subjects). Eligible subjects checked into the clinical unit 2 days after the start of the experiment and collected for 24-hour EPA / DHA pharmacokinetics on the 1st and 1st days after the start of the experiment.

Three doses of pre-emulsion concentrate capsules were further studied in Part B. Subjects from Part A participated in Part B after a washout period of at least 3 weeks.

Part B was a simple-blind, randomized, parallel-group, placebo-controlled study consisting of three dose levels of K85EE pre-emulsion concentrate capsules and a two-week repeated dose period with one dose of LOVAZA®. Within each cohort, at least 8 healthy subjects were randomized to the aggressive treatment group, and at least 2 subjects were given comparable placebo (corn oil, NF 994 mg and D-α tocopherol, USP 6 mg). 1000 mg capsules containing) were randomized. Data from placebo subjects were pooled for analysis. Subjects who checked in to the clinical study unit participated in the test diet 2 days after the start of the experiment and obtained a 24-hour baseline EPA / DHA profile on the 1st and 1st days after the start of the experiment. Subjects left the clinic on day 2 and returned for daily dosing on days 3-12 (short visit as outpatient on day 6). Subjects rechecked into the clinic on the night of day 12, and a 24-hour EPA / DHA profile was taken on day 13.
Subject exited the clinic on day 14 following a procedure involving a test diet and triglyceride sampling.

In summary, subjects were assigned to receive a single dose of one of the following treatments in Part A:

^１処方物（９）：Ｋ８５ＥＥおよび界面活性剤の合計量に基づいて、Ｋ８５ＥＥ ７０重量％、Ｃｒｅｍｏｐｈｏｒ ＥＬＰ ４．５重量％、ポリソルベート８０ ２５．５重量％、ならびに組成物の全重量に基づいて約０．８～０．９重量％水を含む。水中の分散に際して、生じたエマルションの中央粒子サイズは０．１４μｍ（１４０ｎｍ）、ｘ９０は０．４５μｍであった。
^２リンゴジュース中の分散に際して、生じたエマルションの中央粒子サイズは１５０ｎｍであった。
^３最低１０時間の断食。 Part A Dosing / Dosage Summary

¹ Formulation (9): 70% by weight of K85EE, 4.5% by weight of Cremophor ELP, 25.5% by weight of polysorbate 80 based on the total amount of K85EE and surfactant, and about 25.5% by weight based on the total weight of the composition. Contains 0.8-0.9 wt% water. Upon dispersion in water, the central particle size of the resulting emulsion was 0.14 μm (140 nm) and x90 was 0.45 μm.
² The central particle size of the resulting emulsion upon dispersion in apple juice was 150 nm.
³ Fast for at least 10 hours.

In Part B, the subject is subjected to one of a) one of the three dose levels of K85EE pre-emulsion concentrate capsule, b) LOVAZA®, or c) one of four aggressive treatments. Was assigned to. Subjects were blinded as to whether they were receiving aggressive treatment or a corresponding placebo. Aggressive treatment within each cohort: The randomization ratio for placebo was 4: 1. Part B treatment is summarized below.

K85EE pre-emulsion concentrate capsules and LOVAZA® capsules were administered once daily as capsules and placebo as well as the corresponding aggressive treatment in the manner described for Part A. Subjects needed to fast only on PK sampling days.

The pre-emulsion concentrate formulation was similar to Part A. Pre-emulsion concentrate capsules were formed into soft gelatin capsules by direct encapsulation of a mixture containing K85EE oil and a surfactant. K85EE and detergent are blended, about 1 wt% water is added, mixed to form a homogeneous solution and encapsulated using a rotary encapsulation method (gel mass containing gelatin, glycerol and water). ), Formed an oval capsule size 22 or 24 with a reference shell weight of 675 mg, a filling weight of 1200 mg and a minimum sealing thickness of 0.010 inches. Dry the capsules to a hardness of at least 8.5 Newtons (rotate dry in a rotary dryer for about 60 minutes, then tumble dry in a shallow tray, usually at least about twice a day to check the hardness. ), Wash with isopropyl alcohol to remove the lubricating oil used during the process.

Plasma EPA and DHA concentrations were determined according to the method described above.

Concentrations of EPA and DHA in plasma phospholipids were also determined. Thaw the plasma sample and transfer 100 μL to a glass test tube. Add 2 mL methylene chloride, 2 ml methanol and 1 mL distilled water, shake the tube (Multivortex, 2 minutes) and then centrifuge (3000 rpm, 10 minutes) to separate the organic and aqueous layers. 200 μL of organic matter is loaded onto a silica gel G thin layer chromatography plate using an Autospotter. The plate is developed with hexane: ethyl ether: acetic acid (240: 60: 4.5 v / v / v), the plate is removed when the solvent reaches the midline of the plate and dried for about 5 minutes (hood). The plate is then placed in a tank of elemental iodine to detect the phospholipid band (starting point), removed and left for 10-15 minutes to dissipate iodine. Scrape the band into a reaction vial containing 250 μL BF3 methanol and 250 μL hexane. Cap the vial and heat (10 minutes, 100 ° C.). After cooling, 250 μL of water is added, the tube is capped, vortexed for 30 seconds and centrifuged as described above to separate the layers. A 50 μL hexane layer was transferred to a GC (gas chromatographic) vial and according to GC (GC2010, Shimadzu, Columbia MD, capillary column SP2560, 100 m, Superco, Bellefonte PA; 180 ° C. for 1.75 minutes, up to 200 ° C. Analyze by lamp 5 ° C./min, 200 ° C. for 1.75 minutes, lamp 10 ° C./min to 240 ° C., 240 ° C. for 4.5 minutes; hydrogen carrier; or equivalent conditions).

Research results include:

Part A
Tables 3-4 below summarize some plasma AUC and Cmax data for total and free EPA and DHA (corrected for baseline) obtained for regimens in Part A (day 1 visit). ).

１．データは幾何平均（９５％ＣＩ）ＣＶｂ％として報告された。特別の指示の無い限り、各レジメンについてＮ＝１６。
レジメンの手引きは以下の通り。
Ａ－エマルションカプセル１．６８ｇ
Ｂ－液体エマルション１．６８ｇ
Ｃ－ＬＯＶＡＺＡ ４ｇ Table 3 All EPA and DHA-plasma AUC and Cmax (corrected at baseline) ¹

1. 1. Data were reported as geometric mean (95% CI) CVb%. N = 16 for each regimen unless otherwise specified.
The guide for regimen is as follows.
A-emulsion capsule 1.68g
B-Liquid Emulsion 1.68g
C-LOVAZA 4g

１．幾何平均（９５％ＣＩ）ＣＶｂ％。特別の指示の無い限り、各レジメンについてＮ＝１６。
２．ｎ＝１４。
３．ｎ＝１３。
レジメンの手引きは以下の通り。
Ａ－エマルションカプセル１．６８ｇ
Ｂ－液体エマルション１．６８ｇ
Ｃ－ＬＯＶＡＺＡ ４ｇ Table 4 Free EPA and DHA-plasma AUC and Cmax (corrected at baseline) ¹

1. 1. Geometric mean (95% CI) CVb%. N = 16 for each regimen unless otherwise specified.
2. 2. n = 14.
3. 3. n = 13.
The guide for regimen is as follows.
A-emulsion capsule 1.68g
B-Liquid Emulsion 1.68g
C-LOVAZA 4g

Mean Cmax and AUC values for free and total EPA and DHA were several times higher for subjects given emulsion capsules and liquid emulsions when compared to LOVAZA treatment. These PK parameters were twice as high for subjects given liquid emulsions compared to subjects given emulsion capsules. Medium to high inter-subject variability was observed for Cmax and AUC estimates. Inter-subject variability was less for subjects fed emulsion capsules or liquid emulsions compared to LOVAZA treatment. Therefore, the compositions of the present invention can provide better predictability in dosing / dose setting.

Statistical analysis included comparison of dose-normalized and baseline-corrected Cmax and AUC (0-24) values of emulsion capsules, liquid emulsions and LOVAZA regimens from Part A, including the results shown in Table 5. It was.

Table 5 Estimates and 90% CI for comparison of pharmacokinetic (PK) parameters normalized by dose and corrected at baseline on day 1 (after a single dose of prescription in Part A)

Free and total EPA / DHA Cmax and AUC (0-24) values were significantly higher in both emulsion capsules and liquid emulsions compared to 4 g of LOVAZA. Free and baseline-corrected AUC (0-24) values for total EPA and DHA were 10-14 times higher for emulsion capsules and 21-23 times higher for liquid emulsions compared to 4 g of LOVAZA. The 90% CI associated with free and baseline-corrected AUC (0-24) values for all EPA and DHA was completely out of range in the 0.8-1.25 interval.

The Cmax and AUC (0-24) values for free and total EPA / DHA were significantly higher for liquid emulsion formulations than for emulsion capsules. Free and baseline-corrected AUC (0-24) values for total EPA and DHA were 33-52% higher for liquid emulsions compared to emulsion capsules. Although not constrained or limited by theory, it is believed that liquid emulsions are less susceptible to fluctuations in gastrointestinal conditions and digestive activity, including passage, and therefore exhibit higher exposure compared to pre-emulsion concentrate capsules. Be done. This higher exposure can approximate the maximum exposure potentially achievable with the corresponding emulsion capsules. Capsule forms are preferred, for example for providing protection from degradation, as well as ease of use and patient compliance.

Part B
Tables 6 and 7 summarize some plasma AUC and Cmax data for baseline-corrected total and free EPA / DHA obtained for regimens in Part B.

１． 幾何平均（９５％ＣＩ）ＣＶｂ％。
レジメンの手引きは以下の通り。
Ｄ＝エマルションカプセル０．８４ｇ（Ｎ＝１１）。
Ｅ＝エマルションカプセル１．６８ｇ（Ｎ＝８）。
Ｆ＝エマルションカプセル３．３６ｇ（Ｎ＝１０）。
Ｇ＝ＬＯＶＡＺＡ ４ｇ（Ｎ＝９）。
Ｐ＝プラセボ（プールした）（Ｎ＝９）。 Table 6 Pharmacokinetic parameters for total plasma EPA and DHA: Part B (0-24 hours), baseline corrected ¹

1. 1. Geometric mean (95% CI) CVb%.
The guide for regimen is as follows.
D = emulsion capsule 0.84 g (N = 11).
E = Emulsion capsule 1.68 g (N = 8).
F = emulsion capsule 3.36 g (N = 10).
G = LOVAZA 4 g (N = 9).
P = placebo (pooled) (N = 9).

Table 7 Pharmacokinetic parameters of plasma free EPA and DHA: Part B (0-24 hours), baseline corrected ¹

Free and total EPA / DHA Cmax and AUC (0-24) values were generally much lower for the pooled placebo group when compared to exposure from subjects dosed with 3 dose levels of emulsion capsules or LOVAZA. Cmax and AUC (0-24) values increased with increasing dose of K85EE emulsion capsules from 0.84 g to 3.36 g for free and total EPA / DHA. Free and total EPA / DHA Cmax and AUC (0-24) values were higher on day 13 than on day 1, indicating release and total EPA / DHA accumulation after repeated doses of both emulsion capsules and LOVAZA. Cmax and AUC estimates of free and total EPA and DHA showed moderate to high inter-subject variability.

A parametric analysis of the assessment of release and total EPA / DHA accumulation after repeated dosing was performed on each of the Part B regimens and includes the results shown in Table 8.

Table 8 Parametric analysis results for evaluation of release and total EPA / DHA accumulation after repeated dosing of the formulations in Part B

Free and total EPA and DHA AUC (0-24) values were significantly increased on day 13 compared to day 1 for both emulsion capsules and LOVAZA (4 g). The AUC (0-24) values for free and total EPA and DHA on day 13 compared to day 1 were up to 1.26 to 1.95 times for emulsion capsules and 1.67 for LOVAZA 4 g. It increased up to 2.43 times. The 90% CI associated with free and total EPA and DHA AUC (0-24) values was generally out of the 0.8-1.25 interval for the Day 13: 1 comparison. The results show that free and total EPA and DHA are significantly accumulated after 13 days of repeated dosing of emulsion capsules (0.84 to 3.36 g K85EE and 4 g of LOVAZA).

The dose proportions of EPA and DHA (total and free) after repeated dosing of emulsion formulations are assessed and include the results shown in Table 9.

Table 9 Analysis Results for Evaluation of Free and Total EPA / DHA Dose Proportionality After Repeated Dosing of Emulsion Formulations in Part B

There was no significant deviation from dose proportionality for all EPAs and free DHA. Exposure to free EPA after repeated doses was more than proportional to dose, and exposure to total DHA after repeated doses was less than proportional to dose.

Percentages of EPA uptake into plasma phospholipids over a 24-hour measurement period are shown in Table 10 for AUC over a 24-hour period. A similar pattern was observed for Cmax.

Table 10 Incorporation of EPA and DHA into phospholipids-parameters

Table 11 reflects the percentage change from baseline in the mean exposure on day 13 (Cmean calculated from AUC [0-24h] divided by 24).

Table 11

Dose proportionality of Cmean was assessed by point estimation (% CI) of 0.77 (0.55, 0.99) for EPA and 0.67 (0.41 and 0.94) for DHA. A parametric analysis of emulsion treatment options compared to LOVAZA as a reference shows that EPA and DHA uptake (Cmean) is significantly higher for treatment F and DHA uptake is significantly lower for treatment D.

Uptake of EPA and DHA in plasma phospholipids was assessed on days 1, 1, 6, and 13 prior to the dose after the start of the experiment. As shown in Table 12, EPA and DHA increased in all aggressive treatment groups over the dosing period, and EPA increased to a greater extent.

Table 12

EPA and DHA uptake into plasma phospholipids showed an increase in dose correlation, plus an increase on day 13 for the aggressive treatment group. The uptake profile for 4 g of LOVAZA was between those observed for one and two capsule emulsion doses. The increase from baseline in the 24-hour AUC on day 13 was highest at the four capsule emulsion doses (about 8-fold for EPA and about 2-fold for DHA); about 4 g of LOVAZA for EPA. It was double. Uptake measured on days 1, 1, 6, and 13 before the dose after the start of the experiment showed a similar increase in dose correlation. After repeated dosing, uptake of EPA and DHA into phospholipids increased above baseline in all aggressive treatment groups. The increase was dose-dependent for the EPA, and an 8-fold increase was observed for the capsule dose of 4 emulsions compared to a 4-fold increase for 4 g of LOVAZA. To a lower extent, DHA uptake was also increased.

In addition, it was found that food affects exposure to EPA after dosing with 4 g of LOVAZA, but this does not happen with pre-emulsion concentrate capsules. Significant increases in AUC (0-8) values were observed for free and total EPA when 4 g LOVAZA was administered with a high fat diet compared to the fasted state (Table 13). When a high-fat diet is administered with pre-emulsion concentrate capsules compared to fasting conditions, the food effect is free and total EPA
No AUC (0-8) values were observed. Although not constrained or limited by theory, it is believed that the LOVAZA 4g formulation helps the emulsifying action of bile salts during food digestion. In contrast, the pre-emulsified concentrate, which was already supplied as an emulsifiable formulation, did not appear to serve bile salts for absorption or require further emulsification.

Table 13

In the above clinical study, compared to non-emulsified LOVAZA products, the emulsion pre-concentrate composition was exposed to EPA and DHA, as well as the uptake of EPA and DHA into phospholipids. Shows that it provided an essential increase. This increased bioavailability can provide increased efficacy (eg, increased reduction in triglycerides) compared to non-emulsified LOVAZA products in subjects in need of treatment. Thus, the pre-emulsified concentrate capsules of the present invention can allow lower doses and / or fewer dosing units for the same or similar efficacy as the corresponding non-emulsified omega-3 fatty acid oils. Therefore, less ω-3 fatty acid oil is required to achieve efficacy, which can reduce environmental impact, exposure to undesired components of the oil, side effects of therapy, caloric intake and cost. ..

All publications, including but not limited to patents and patent applications cited herein, are incorporated herein by reference as if each individual publication were fully described. Is incorporated herein by reference, as if indicated specifically and individually.

Claims (12)

Based on the total weight of the ω-3 fatty acid oil and the surfactant, it comprises 60-85% by weight of the ω-3 fatty acid oil, PEG35 castor oil and 80 [polyoxyethylene (20) monooleate sorbitan]. An orally administered pre-emulsion concentrate composition comprising 15-40% by weight of surfactant. Based on the total weight of the ω-3 fatty acid oil and the surfactant, it comprises 66-88% by weight of the ω-3 fatty acid oil, PEG35 castor oil and 80 [polyoxyethylene (20) sorbitan monooleate]. An orally administered pre-emulsion concentrate composition comprising 10-30% by weight of surfactant. The ω-3 fatty acid oil is a) ω-3 polyunsaturated free fatty acid, b) ester of polyunsaturated free fatty acid with glycerol, c) polyunsaturated free fatty acid and primary alcohol, second. The orally administered pre-emulsion concentrate composition according to claim 1 or 2 , comprising an ester of a tertiary alcohol or a tertiary alcohol, and d) an omega-3 fatty acid selected from a mixture thereof. The orally administered pre-emulsion concentrate composition according to any one of claims 1 to 3, wherein the ω-3 fatty acid oil contains at least 40% by weight of one or more ω-3 fatty acids. thing. The pre-emulsion concentrate composition to be orally administered according to any one of claims 1 to 4, wherein the ω-3 fatty acid oil contains at least 50% EPA and DHA by weight. The pre-emulsion concentrate composition to be orally administered according to any one of claims 1 to 5 , wherein the ω-3 fatty acid oil contains 5 to 100% EPA by weight. The pre-emulsion concentrate composition to be orally administered according to any one of claims 1 to 6 , wherein the ω-3 fatty acid oil contains 5 to 100% DHA by weight. The pre-emulsion to be orally administered according to any one of claims 1 to 7 , wherein the ω-3 fatty acid oil contains EPA and DHA in a weight ratio of EPA: DHA of 99: 1 to 1:99. Concentrate composition. The pre-emulsion concentrate composition to be orally administered according to any one of claims 1 to 8 , wherein the ω-3 fatty acid oil is the only active ingredient in the composition. The pre-emulsion concentrate composition to be orally administered according to any one of claims 1 to 9 , further comprising a co-solvent. The orally administered pre-emulsion concentrate composition according to claim 10 , wherein the co-solvent is selected from C _1-4 alcohol, C _12-22 free fatty acid, and a mixture thereof. The orally administered pre-emulsion concentrate composition according to claim 10 or 11 , wherein the composition comprises 0.1-5% by weight of the cosolvent based on the weight of the composition.